Cardiac myocytes size increases through either longitudinal growth by series addition of sarcomeres or cross-sectional growth by parallel addition of sarcomeres. How cardiac myocytes incorporate sarcomeres is dependent on loading condition and resultant cytoskeletal changes. The activation of longitudinally-oriented cadherin-beta-catenin signaling pathways may recruit signal molecules to the polar plasma membrane and lead to series addition of sarcomeres, progressive cell lengthening and eventually pump failure. Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates beta-catenin on serine and threonine, regulating cytoplasmic beta-catenin level and controlling gene expression. Our studies on genetic hypertension and myocardial infarction have shown that cadherin-beta-catenin signaling is activated during myocyte lengthening. The long-term objective of this proposal is to understand how cardiac myocyte shape and polarity is regulated during cardiac hypertrophy and failure. The short-term goal is to define the roles of cadherin-beta-catenin mediated signaling pathways during eccentric hypertrophy and myocyte lengthening. We hypothesize that activation of the beta-catenin signaling pathway by GSK-3beta inhibition triggers myocyte lengthening and eccentric hypertrophy. This proposal focuses on the GSK-3beta mediated activation of beta-catenin signaling and resultant myocyte shape and polarity changes during myocyte legnthening. We will determine kinase activity of GSK-3beta and beta-catenin signaling in cardiac myocytes after MI. More importantly we will manipulate GSK-3beta activity to determine its role in beta-catenin signaling, myocyte shape and polarity. Finally we will examine how beta-catenin signaling affects cardiac gene expression, myocyte shape and polarity. These studies will further our understanding of myocyte shape and polarity regulation in cardiac hypertrophy and failure and identify key molecules involved in myocyte shape and polarity regulation for future genetic manipulation and gene therapy.